Date Published: January 23, 2017
Publisher: Public Library of Science
Author(s): Jineta Banerjee, Mary E. Sorrell, Pablo A. Celnik, Galit Pelled, Jonghoon Choi.
Repetitive Transcranial Magnetic Stimulation (rTMS) has been successfully used as a non-invasive therapeutic intervention for several neurological disorders in the clinic as well as an investigative tool for basic neuroscience. rTMS has been shown to induce long-term changes in neuronal circuits in vivo. Such long-term effects of rTMS have been investigated using behavioral, imaging, electrophysiological, and molecular approaches, but there is limited understanding of the immediate effects of TMS on neurons. We investigated the immediate effects of high frequency (20 Hz) rTMS on the activity of cortical neurons in an effort to understand the underlying cellular mechanisms activated by rTMS. We used whole-cell patch-clamp recordings in acute rat brain slices and calcium imaging of cultured primary neurons to examine changes in neuronal activity and intracellular calcium respectively. Our results indicate that each TMS pulse caused an immediate and transient activation of voltage gated sodium channels (9.6 ± 1.8 nA at -45 mV, p value < 0.01) in neurons. Short 500 ms 20 Hz rTMS stimulation induced action potentials in a subpopulation of neurons, and significantly increased the steady state current of the neurons at near threshold voltages (at -45 mV: before TMS: I = 130 ± 17 pA, during TMS: I = 215 ± 23 pA, p value = 0.001). rTMS stimulation also led to a delayed increase in intracellular calcium (153.88 ± 61.94% increase from baseline). These results show that rTMS has an immediate and cumulative effect on neuronal activity and intracellular calcium levels, and suggest that rTMS may enhance neuronal responses when combined with an additional motor, sensory or cognitive stimulus. Thus, these results could be translated to optimize rTMS protocols for clinical as well as basic science applications.
Transcranial Magnetic Stimulation (TMS) is a non-invasive method of neural activation, currently used as a therapeutic intervention in neurological disorders like depression [1, 2], and migraine ; and being investigated for clinical applications in epilepsy [4, 5], movement disorders , stroke [7, 8], brain injury , and schizophrenia [10, 11]. It is also frequently used as an investigative tool for basic neuroscience [12–17]. Numerous studies with single pulse TMS (sTMS) as well as repetitive TMS (rTMS) have demonstrated that TMS effects can persist for as long as 6 months after the cessation of treatment. Indeed, both clinical [18, 19] and pre-clinical [20–23] studies suggest that TMS can reshape neuronal connections leading to long-lasting changes (neuroplasticity). Nevertheless, the cellular mechanisms underlying these TMS-induced long-term plasticity changes remain poorly understood. This lack of understanding has led to high variability in the responses of patients to TMS treatment in the clinical setting. Therefore, elucidating the cellular mechanisms involved would aid in understanding the neuronal basis of the effect of different rTMS protocols and design better treatment protocols.
All animal procedures were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and approved by the Johns Hopkins University Animal Care and Use Committee.
In the present study we report the immediate effects of TMS on acute brain slices at a single cell resolution using a commercial TMS system and clinically relevant high frequency (20 Hz) rTMS protocols. Our results show that each TMS pulse causes an immediate and transient activation of VGSCs in the soma of cortical neurons. Furthermore, a short duration of rTMS significantly increases the steady state current of the neurons, induces action potentials, and modulates spike timing in these neurons. Longer duration rTMS stimulations lead to delayed increases in intracellular calcium in primary cortical neurons.